Compositions of high specific activity 117mSn and methods of preparing the same

ABSTRACT

Compositions of high specific activity  117m Sn with specific activity of greater than 100 Ci/g Sn and methods of producing the same. The method includes exposing  116 Cd to an α-particle beam of sufficient incident kinetic energy and duration to convert a portion of the  116 Cd to  117m Sn to form an irradiated material. The irradiated material is dissolved to form an intermediate solution containing  117m Sn and  116 Cd. The  117m Sn is separated from the  116 Cd to yield high specific activity  117m Sn.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional application of thenon-provisional patent application Ser. No. 12/344,340, which was filedon Dec. 26, 2008 and which is expressly incorporated by reference hereinin its entirety.

BACKGROUND

The present invention relates to medically useful radioisotopes, andparticularly to no-carrier-added (NCA) radioisotopes of tin and methodsof preparing NCA radioisotopes of tin.

The use of beta particle-emitting radioisotopes for applications innuclear medicine, oncology and interventional cardiology is rapidlyincreasing because of the availability of new pharmaceutical targetingapproaches, which effectively concentrate or localize the radioactivevector at the target site with low uptake in non-target tissues. In thismanner, the energy released from decay of the radioisotope can belocalized for killing cells at the target site, such as the cells of atumor. In this regard, the use of such radiopharmaceuticals has beenshown to be effective in treating a variety of tumors and cancers.

Approximately 320,000 new cases of bone cancer are reported annually inthe United States. A complex of ^(117m)Sn (Sn⁴⁺) chelated todietheylenetriamine pentaacetic acid (DTPA) has been used in clinicaltrials as a bone seeking pain reliever for metastatic bone cancers whichare currently untreatable and fatal. The ^(117m)Sn complex does notsedate the patient, as do narcotic drugs, and provides selectiveradiation to the metastatic bone tumor while providing little radiationto the bone marrow. Consequently, the ^(117m)Sn complex does notinterfere with the bone marrow's ability to fight infection and does notinterfere with blood clotting.

The nuclear-physical and biochemical properties of ^(117m)Sn haveenabled its useful application in nuclear medicine. The radioisotope^(117m)Sn possesses a relatively short 14-day half-life, a gammaemission of 158 keV (87%) and a high yield of short-range conversionelectrons with energies of 126 keV (64%), 152 keV (26%) and 129 keV(11%).

The effectiveness of a radioisotope that emits particles, such as betaparticles, can be improved if the specific activity of a radioisotopeconstruct is increased and if a construct can be designed tospecifically target a site of interest. However, specific activity isoften limited by the available production methods for the isotope andthe subsequent purification procedure. Therefore, a recognized needexists in the art for medically useful radionuclides with high specificactivities that are targetable and have little or no effect on healthytissue or organs.

A common method for the production of the radioisotope ^(117m)Sn isthrough a “direct” method in a nuclear reactor via thermal neutroncapture [¹¹⁶Sn(n,γ) ^(117m)Sn] or via non-elastic neutron scattering[¹¹⁷Sn(n, n′, γ) ^(117m)Sn] reactions. Because the nonradioactive targetatoms and radioactive product atoms are not chemically separable, theradioactive ^(117m)Sn is diluted with significant amounts of the targetisotope of tin. This excess of non-radioactive tin atoms therefore actslike a carrier, which inherently reduces the specific activity of thesample. With 97% or greater enriched-¹¹⁷Sn as a target, maximum specificactivities of up to about 20 to about 23 Ci/g have been achieved usingthermal neutrons, [¹¹⁷Sn (n, n′γ) ^(117m)Sn]. This is substantially lessthan the theoretically possible specific activity of about 82,000 Ci/g,thereby leaving much room for improvement. In addition, the muchlonger-lived ¹¹³Sn isotope may be produced from the thermal neutron“direct” method with the naturally-occurring ¹¹²Sn isotopic impurity.The radioactive ¹¹³Sn isotope has a half-life of 115 days and two higherenergy gamma rays of 392 keV (64%) and 255 keV (2%). The radioisotope¹¹³Sn is generally considered harmful for nuclear medicine applications,because of the potential for extended patient exposure to radiation.

Conversely, there are several known methods of producing NCA ^(117m)Sn.For example, reactions utilizing non-tin target atoms may employproton-induced, ³He-particle-induced, or α-particle-induced reactions oncadmium and indium targets. Many reactions, such as ¹¹⁴Cd(³He, γ),¹¹⁴Cd(α,n), ¹¹⁶Cd(³He, 2n), ¹¹⁶Cd(α,3n), ¹¹⁵In(d, γ), ¹¹⁵In(³He, p), and¹¹⁵In(α, pn), are known to lead to the formation of NCA ^(117m)Sn, butare generally accompanied by production of some amount of the ¹¹³Snradioisotope and other by-products.

Moreover, in addition to the manner of radioisotope generation, anothermajor hindrance with producing NCA ^(117m)Sn with high specific activityis the absence of an effective method for separating ^(117m)Sn from thetarget material. Efficiently separating small quantities of a desiredspecies from a much larger matrix, i.e. debulking, is notoriouslydifficult using conventional separation methods, such as chromatographyor extraction. Historically, this very aspect of radionuclidepurification provoked the use of a carrier, thereby rendering sampleswith reduced specific activity because of dilution by non-radioactivetarget atoms from the carrier.

Therefore, in view of the foregoing, a need exists for the productionand isolation of NCA, high specific activity ^(117m)Sn acceptable foruse in radiopharmaceuticals.

BRIEF SUMMARY

In accordance with an embodiment of the invention, a composition ofmatter comprises ^(117m)Sn having a specific activity of greater than100 Ci/g Sn and a ratio of mass of Cd to mass of Sn less than 15,000:1.

In accordance with another embodiment of the invention, a productcomprising high specific activity ^(117m)Sn is prepared by a method thatincludes exposing isotopically-enriched ¹¹⁶Cd to a α-particle ion beamwith an incident kinetic energy of about 30 MeV to about 60 MeV toconvert a portion of the ¹¹⁶Cd target to ^(117m)Sn to form an irradiatedmaterial. The irradiated material is dissolved to form an intermediatesolution comprising ¹¹⁶Cd and ^(117m)Sn. The ^(117m)Sn is separated fromthe ¹¹⁶Cd via ion exchange chromatography by preparing an ion exchangeresin column, loading the intermediate solution onto the ion exchangeresin column, eluting the ^(117m)Sn and the ¹¹⁶Cd from the ion exchangeresin column with an eluent solution and collecting at least a portionof the eluent discharged from the ion exchange resin column.

In accordance with another embodiment of the invention, a productcomprising high specific activity ^(117m)Sn is prepared by a method thatincludes exposing isotopically-enriched ¹¹⁶Cd to a α-particle ion beamwith an incident kinetic energy of about 30 MeV to about 60 MeV toconvert a portion of the ¹¹⁶Cd target to ^(117m)Sn to form an irradiatedmaterial. The irradiated material is dissolved to form an intermediatesolution comprising ¹¹⁶Cd and ^(117m)Sn. The ^(117m)Sn is separated fromthe ¹¹⁶Cd via partitioning the intermediate solution between an organicsolvent layer and an aqueous layer.

In accordance with another embodiment of the invention, a method ofpreparing a high-specific-activity ^(117m)Sn composition includesexposing an isotopically-enriched ¹¹⁶Cd target to a α-particle ion beamwith an incident kinetic energy of about 30 MeV to about 60 MeV toconvert a portion of the ¹¹⁶Cd target to ^(117m)Sn to form an irradiatedmaterial. The irradiated material is dissolved to form an intermediatesolution comprising ¹¹⁶Cd and ^(117m)Sn. The ^(117m)Sn is separated fromthe ¹¹⁶Cd via ion exchange chromatography by preparing an ion exchangeresin column, loading the intermediate solution onto the ion exchangeresin column, eluting the ^(117m)Sn and the ¹¹⁶Cd from the ion exchangeresin column with an eluent solution and collecting at least a portionof the eluent discharged from the ion exchange resin column.

In accordance with another embodiment of the invention, a method ofpreparing a high-specific-activity ^(117m)Sn composition includesexposing an isotopically-enriched ¹¹⁶Cd target to a α-particle ion beamwith an energy of about 30 MeV to about 60 MeV to convert a portion ofthe ¹¹⁶Cd target to ^(117m)Sn to form an irradiated material. Theirradiated material is dissolved to form an intermediate solutioncomprising ¹¹⁶Cd and ^(117m)Sn. The ^(117m)Sn is separated from the¹¹⁶Cd via partitioning the intermediate solution between an organicsolvent layer and an aqueous layer to produce a product enriched in^(117m)Sn.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate various embodiments of theinvention and, together with a general description of the inventiongiven above and the detailed description of the embodiments given below,serve to explain the embodiments of the invention.

FIG. 1 is a cross-sectional view of a simplified target.

FIG. 2 is a cross-sectional view of the target layer as shown in FIG. 1.

FIG. 3 is a diagrammatic view of a simplified cyclotron with internaland external target placements.

DETAILED DESCRIPTION

The method and processes describe herein provide for the generation andisolation of NCA ^(117m)Sn compositions at commercially viable yieldsand with high specific activities that have not been achieved by othermethods known in the art. Briefly, the process includes preparing one ormore targets comprising a thin-layer of enriched cadmium (¹¹⁶Cd). Thetarget comprising the enriched ¹¹⁶Cd is irradiated with a beam ofα-particles to form ^(117m)Sn. The irradiated cadmium layer is dissolvedin a strong acid and the solution is subjected to a purification processto separate the desired ^(117m)Sn from the matrix of the irradiatedtarget.

FIG. 1 depicts a cross-section of a target 10 comprising a thin-layer ofa target material 12, an optional barrier layer 13, and a substrate 14.The composition of the target material 12 is selected to react withα-particles having energies ranging from 20 MeV to about 60 MeV to formradionuclides suitable for use in diagnostic or therapeuticradiopharmaceuticals. In one embodiment, isotopically-enriched cadmiumis used for preparing NCA, high specific activity ^(117m)Sn. In aspecific embodiment, the isotopically-enriched isotope of cadmium is¹¹⁶Cd, which can undergo the nuclear reaction ¹¹⁶Cd(α,3n) ^(117m)Sn toproduce NCA, high specific activity ^(117m)Sn.

The target material 12 is preferably as chemically pure as commerciallypossible. The use of a target material that has a minimal amount ofchemical impurities facilitates subsequent isolation and purification ofthe radionuclide of interest. To produce NCA ^(117m)Sn characterized bya high specific activity, the target material should have a minimalamount of carrier (i.e., tin) impurities and/or other chemicalimpurities. These types of impurities may be difficult to chemicallyseparate from the product. For example, the target material may beenriched ¹¹⁶Cd with greater than 99.9 wt % elemental purity and greaterthan 98 wt % isotopic purity.

The substrate 14, which supports the target material 12, is preferablycomposed of material that is chemically inert and separable from thetarget material 12 to allow for recovery and recycling of the targetmaterial 12. Additionally, the material from which barrier layer 13 andsubstrate 14 are comprised should be separable from the desiredradionuclide produced during subsequent irradiation. The substrate 14preferably has a melting point and a thermal conductivity that is atleast about equal to the melting point and the thermal conductivity ofthe target material 12. One additional aspect to consider is for thebarrier layer 13 and the substrate 14 to produce only a minimal amountof radioactive byproducts. Cadmium has a melting point (m.p.) of 321° C.and a thermal conductivity (k) of 97 W/mK. In one embodiment, thesubstrate is composed of copper, which has a melting point of 1085° C.and a thermal conductivity of 401 W/mK. In other embodiments, thesubstrate 14 can be composed of aluminum (m.p.=660° C., k=237 W/mK) orsilver (m.p.=961° C., k=429 W/mK). Moreover, the configuration (e.g.,shape, thickness, etc.) of the substrate 14 may exist in manygeometrical configurations. Generally, the substrate 14 is shaped tofacilitate use in a particular target holder and is preferably thickenough to provide adequate mechanical support to the target material 12during irradiation.

Prior to forming a layer of target material 12 on the surface 14 a ofsubstrate 14, one or more additional layers, such as barrier layer 13,may be applied to the surface 14 a. Barrier layer 13 may range from onlya few microns to tens of microns in thickness. Useful attributes ofbarrier layer 13 may include serving as a protective layer to theunderlying substrate 14 during the subsequent removal of the targetmaterial 12 by an etchant. This attribute inhibits leaching of thesubstrate 14 into the etchant when the target material 12 is removed.Additionally, barrier layer 13 may inhibit the absorption of targetmaterial and the produced ^(117m)Sn into the surface 14 a of substrate14. This attribute prevents losses in activity. Therefore, exemplarymaterials for barrier layer 13 are preferably inert or kinetically-slowto react with strong acid etchants, such as hydrochloric acid. Forexample, barrier layer 13 may be prepared from suitable materials likenickel, rhodium or gold.

The barrier layer 13 and the layer of target material 12 can be formedon the surface 14 a by a variety of methods, such as electroplating.Electroplating is achievable by any deposition technique known by thoseof ordinary skill in the art to achieve the desired areal density of thetarget material. For example, the areal density of enriched ¹¹⁶Cd to beelectroplated ranges from about 50 mg/cm² to about 70 mg/cm². As anotherexample, the areal density of enriched ¹¹⁶Cd electroplated is about 55mg/cm².

The optimal thickness of the enriched ¹¹⁶Cd layer of target material 12may vary depending on the specific target material used, thecharged-particle beam energy and current, and the orientation of thetarget material 12 with respect to the beam during subsequentirradiation. In general, however, the thickness, T, of the layer oftarget material 12, as measured normal to the surface 12 a of the targetmaterial 12, is preferably sufficient to result in a projectedthickness, T_(eff), which is sufficient to minimize the activation ofthe backing material 14. The optimization of the thickness may also takeinto account factors, such as cost per unit mass of the target material12 and efficiency for heat transfer from the target material 12 to thesubstrate 14 during irradiation. As depicted in FIG. 2, the projectedthickness, T_(eff), refers to the thickness of the target layer measuredin the direction of travel of the impinging ion beam 16 duringirradiation. The projected thickness can be determined based on thenormal thickness, t, and the angle θ at which the surface 12 a of thetarget material 12 is oriented relative to the pathway of ion beam 16.Generally, for cyclotrons, the angle θ may vary between about 0.5° toabout 2° for internally positioned targets and from about 5° to about25° for externally positioned targets.

The optimal thickness of the target material layer can be determined bycalculating a thickness T sufficient to reduce the α-particle beamkinetic energy to a desired level at the exit side of the targetmaterial 12. As stated above, excessive activation of the backingmaterial 14, as well as any barrier layer, if present, is preferablyminimized. For example, in one embodiment, the α-particle beam kineticenergy is reduced to about 20 MeV at the exit side of the targetmaterial 12. In view thereof, the effective thickness, T_(eff), is about300 μm to about 450 μm, which correspond to a thickness, T, of about 50μm to about 80 μm for an incident α-particle ion beam angle θ equal to10° and kinetic energy of 47.3 MeV. These ranges may vary based otherfactors, such as costs of material, heat transfer considerations andoverall yield of the process.

The target 10, while being irradiated, is cooled by a cooling mediumflow. The temperature and flow rate of the cooling medium are controlledto maintain the temperature of the exposed target layer surface 12 a toless than about 200° C. For example, the temperature of the exposedtarget layer surface 12 a is between 150° C. and 200° C. A flow sensorcan be interlocked with the accelerator such that the accelerator shutsdown if cooling medium flow is reduced to below a predeterminedsetpoint.

The target material 12 is irradiated with an accelerator beam ofpositive ions, in this instance α-particles, to form the radionuclide ofinterest. The particular accelerator design can include, for example,orbital accelerators such as cyclotrons, or linear accelerators.

With reference to FIG. 3, irradiation of a target may be achieved usinga cyclotron 20. The cyclotron 20 accelerates α-particles in a spiralpath 22 inside two semicircular flat metallic cylinders or dees 24,which are placed in a flat vacuum chamber 26 to produce the ion beam 16.The two dees 24 are connected to a high frequency alternating voltage(not shown.) The dees 24 and the vacuum chamber 26 are placed betweenthe two poles of a magnet (not shown) so that the magnetic fieldoperates upon the α-particles that make up the ion beam 16 to constrainit to flat spiral paths 22 inside the dees 24. At the gap 30 between thedees 24, the α-particles experience an acceleration due to the potentialdifference between the dees 24. The ion beam 16 originates at the ionsource at the center of the cyclotron 20, and as the ions spiral outwardin the dees 24 they acquire a constant increase in energy for eachpassage across the gap between the dees 24. There can be two generallocations for an internal beam target; the target can be place eitherbefore or after the deflector electrode 32. The target 10′ can belocated either inside the vacuum chamber 26 before the deflectorelectrode 32 or after extraction of the ion beam 16 from the spiral path22 by a deflector electrode 32 into an evacuated chamber, as representedby target 10.

The ion beam 16 can be generated in a low or medium energy accelerator,which, as used herein, includes accelerators capable of generating anion beam of α-particles having incident kinetic energies within a rangeof about 30 MeV to about 60 MeV and an ion beam current in a range of atleast about 10 μA.

However, the accelerator need not be capable of generating an ion beamover the entire energy range and current range. The accelerator can becapable of generating ion beam energies in excess of 60 MeV, providedthe accelerator is also capable of generating ion beams within the about30 MeV to about 60 MeV range. The ion beam current useful for anyspecific embodiment of this invention is not limited to any specificamount. Instead, the ion beam current at a particular energy or energyrange will generally be limited by accelerator capabilities and/or byheat-transfer considerations. Moreover, the ion beam current can besufficient to produce an amount of radionuclide (as measured in curies)that is sufficient for clinical use in a radiopharmaceutical imaging ortherapeutic agents or compositions.

The ion beam 16 may impinge the target 10 over an impingement area thatsubstantially matches, but is slightly less than, the target layersurface area. Both the target layer surface area and the matching ionbeam strike or impingement area are preferably as small as possiblewithin heat transfer considerations. For example, the target layersurface area may be 7.5 cm×2.5 cm, 11 cm×2 cm, or 12.4 cm×1.6 cm.

The amount of time over which the target 10 is irradiated may bevariable. Irradiation of the target nuclide at a particular ion beamcurrent can generally be continued for a time sufficient to generate thedesired quantities or amounts of radioactivity of the radionuclide ofinterest that are sufficient for use in preparing radiodiagnostic andradiotherapeutic agents or compositions suitable for clinicalapplications. The time required will vary depending on the nuclearreaction being effected, the ion beam energy and ion beam current.Typically, the irradiation time may vary between 4 to 24 hours.

In general, the specific activity of the ^(117m)Sn composition at theend of bombardment significantly exceeds the near saturation pointprovided by the “direct” method, about 20 to about 23 Ci/g Sn, asdescribed above. To be commercially viable, the α-particle bombardmentof an enriched ¹¹⁶Cd target should provide for a specific activity ofthe ^(117m)Sn composition of greater than 100 Ci/g Sn at the end ofbombardment (EOB). In one example, the specific activity may be about500 Ci/g to about 25,000 Ci/g Sn at EOB. As another example, thespecific activity may be about 800 Ci/g to about 20,000 Ci/g Sn at EOB.As yet another example, the specific activity may be about 1,000 Ci/g toabout 5,000 Ci/g Sn at EOB.

The very nature of radioactivity may affect the specific activity of theNCA ^(117m)Sn product. After terminating the α-particle bombardment ofthe target layer 12, the production of ^(117m)Sn from ¹¹⁶Cd ceases.Meanwhile, ^(117m)Sn continuously decays with a half-life of 14.0 daysto stable ¹¹⁷Sn. Thus, the radioactive decay affects the specificactivity of the final isolated product. Moreover, delay time from EOB toprocessing, the time for performing a purification method, samplepreparation, shipping time, etc. should all be considered in anydetermination of specific activity following EOB.

After irradiation, the target 10 is etched by a strong acid solution todissolve the target layer 12, thereby separating the target layer 12from the substrate 14 and producing an intermediate solution thatcontains ¹¹⁶Cd, ^(117m)Sn, other radionuclides generated in the targetmatrix and other possible impurities, such as the nickel, iron, lead,the barrier layer material or the substrate material. This intermediatesolution may be treated with other reagents, such as precipitatingagents, oxidants, or ligands, such as chelating agents, to facilitatepurification. Strong acids may include hydrochloric acid, nitric acid orhydrobromic acid, for example. Treatment reagents may include hydrogenperoxide, bromine water, bromates or peracids, for example. The targetlayer 12 may be dissolved in hydrochloric acid and treated with hydrogenperoxide. Alternatively, the intermediate solution may be evaporated todryness or near dryness prior to purification.

For use as a pharmaceutical agent, the radionuclide must meet certainpurity guidelines. As such, chemical purification of the intermediatesolution comprising ^(117m)Sn may be achieved via a variety ofapproaches to provide a product enriched in ^(117m)Sn and diminished incadmium and other impurities. Distillation, precipitation, extraction,or ion exchange column chromatography are all generally applicablemethods for isolating a product enriched in ^(117m)Sn with adequatepharmaceutical purity. A distillation purification may be achieved byutilizing the higher vapor pressure of SnCl₄ relative to the chloridesof cadmium and other elements present in the target matrix.Co-precipitation with other metals, such as iron, can be used to isolatetin. Liquid-liquid extractions may be performed using two immisciblesolvents, such as hexones and aqueous solutions. Column chromatographymay be effective using ion exchange resins as the stationary phase.

Ion exchange chromatography is suitable to achieve the desired purity of^(117m)Sn. The ion exchange resin used to form a separation column maybe pretreated with an oxidant prior to use. For example, a mixture of anion exchange resin, slurried in a suitable solvent, may be treated withan oxidant solution, thereby forming a pretreated resin. Pretreating theresin may inhibit the reducing activity of an ion exchange resin. Forexample, without this pretreatment, a Sn⁴⁺ species in the sample may bereduced to a Sn²⁺ species by the ion exchange resin, which then maybecome difficult to elute from the resin. From a thermodynamicsperspective, the oxidant or oxidizing reagent must at least have astandard reduction potential, which is more positive than 0.15 V, thereduction potential of Sn⁴⁺ to Sn²⁺. In one embodiment, bromate, whichhas a standard reduction potential of about 1.4 V, is used to pretreatthe ion exchange resin.

In one example, AG1X4 resin, commercially available from Bio-RadLaboratories, Hercules, Calif., is slurried in 9 N hydrochloric acid toform a mixture. While the resin slurry is stirred, solid NaBrO₃ is addedto pretreat the resin. Afterwards, an ion exchange resin column may beprepared with the pretreated resin.

The dissolved target layer sample may be loaded onto the pretreatedresin column and eluted with an appropriate mobile phase, such as 0.1 NHNO₃ or other dilute solutions of strong acids. Fractions of the elutedmobile phase may be collected, as is commonly performed by those skilledin the art. After elution, the fractions containing the product enrichedin ^(117m)Sn may be concentrated before utilizing the radioisotope forimaging or therapeutic purposes. Any fractions containing ^(117m)Sn withinsufficient purity, such as those contaminated with substrate materialor target material, may be collected, concentrated and subjected toanother purification process. The products enriched in NCA ^(117m)Snprepared according to embodiments of the invention have specificactivities previously unattainable by the “direct” method and withpurity levels suitable for medical uses, such as radiopharmaceutical orimaging compositions.

It should be noted, the specific activity of a product enriched in^(117m)Sn is a function of the specific activity existing at the end ofbombardment, the time having elapsed since the end of bombardment, anyintroduction of cold tin to the sample during processing andcombinations thereof. Therefore, in view of the nature of radioactivedecay, it is advantageous to limit the time between the end ofbombardment and actual use. If a sample possessing a specific activityof a certain range is desirable, then time delay after bombardment,processing time and shipping time must be considered.

The high specific activity NCA ^(117m)Sn product prepared according tothe embodiments of the invention may be useful for therapeutic ordiagnostic purposes. Radiopharmaceutical compositions may be preparedusing the high specific activity NCA ^(117m)Sn product in combinationwith ligands, such as chelators or targeting molecules. For example,1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) ordiethylene triamine pentaacetic acid (DTPA) may be used to formradiopharmaceutical compositions with high specific activity NCA^(117m)Sn.

As used herein, a ligand may be an atom, ion, or molecule that bonds toa central metal, and generally involves the formal donation of one ormore of its electrons. The metal-ligand bonding may range from covalentto more ionic. Furthermore, the metal-ligand bond order can range fromone to three. Chelators are bi- or multidentate ligands and are oftenorganic compounds. A chelator forms a chelate complex with a metalthrough a process known as complexation, in which the metal ion is boundto two or more atoms of the chelating agent. A targeting molecule is atype of ligand that demonstrates an affinity or selectivity toward adesired biological target. Biological targets may include specific celltypes, receptors, antigens, and the like. Exemplary targeting moleculesinclude other types of ligands, such as proteins, antibodies, etc. Insome instances, a pharmaceutical ligand may be complex structure derivedfrom the combination of two or more species of ligands, such as anantibody covalently bonded to a chelator.

The metallic burden is an additional aspect that should be consideredwhen the high specific activity NCA ^(117m)Sn product, preparedaccording to the embodiments of the present invention, is to be used forpreparing a radiopharmaceutical composition. Excessive levels ofmetallic impurities, such as cadmium, may compete with, interfere withor inhibit the desired binding of a ligand to the ^(117m)Sn. Inaddition, it should be appreciated that the level of metallic impuritiesmay vary depending on the chosen purification method. In one embodiment,the product enriched in NCA ^(117m)Sn has a cadmium concentration lessthan 5,000 mg/L and a ratio of the mass of Cd to the mass of Sn lessthan 15,000:1. In another embodiment, the product enriched in NCA^(117m)Sn has a cadmium concentration less than 1,000 mg/L and a ratioof the mass of Cd to the mass of Sn less than 1,000:1. In yet anotherembodiment, the product enriched in NCA ^(117m)Sn has a cadmiumconcentration less than 50 mg/L and a ratio of the mass of Cd to themass of Sn less than 100:1.

It is convenient to measure a metallic impurity level relative to theamount of ^(117m)Sn, measured in millicuries (mCi), in the high specificactivity NCA ^(117m)Sn product. The metallic impurities may include, butare not limited to cadmium, iron, copper, lead, nickel and zinc. Forexample, one sample of high specific activity NCA ^(117m)Sn productsuitable for use in a radiopharmaceutical composition, preparedaccording to the embodiments of the present invention, had a cadmiumcontent less than 20 μg/mCi, an iron content less than 2 μg/mCi and eachother metal present in the sample was less than 3 μg/mCi, per species.

One suitable radiopharmaceutical composition, ^(117m)Sn (Sn⁴⁺) DTPA(diethylene triamine pentaacetic acid), which is useful for thetreatment of bone tumors and pain associated with bone cancer, may beprepared using the high specific activity NCA ^(117m)Sn product asdisclosed herein. After the ion exchange column chromatographypurification, the fractions containing the product enriched in ^(117m)Snmay be concentrated to dryness and the residue dissolved in a minimalamount of concentrated hydrochloric acid to form a solution of^(117m)SnCl₄. A reducing agent may be added, such as cold metallic tin,to reduce the Sn⁴⁺ to the Sn²⁺ oxidation state, thus forming a solutionof ^(117m)SnCl₂. Solid DTPA may be added to this solution of^(117m)SnCl₂ in a molar amount of about 1 to about 3, DTPA to^(117m)SnCl₂. For example, the molar amount of DTPA to ^(117m)SnCl₂ maybe about 1 to about 1.2. After permitting the DTPA to react with^(117m)SnCl₂ to form ^(117m)Sn (Sn²⁺) DTPA, the solution may be oxidizefrom ^(117m)Sn (Sn²⁺) DTPA to ^(117m)Sn (Sn⁴⁺) DTPA, either by exposureto air or by treatment with an oxiding agent, such as hydrogen peroxide,for example. The ^(117m)Sn (Sn⁴⁺) DTPA complex may be isolated as asolid.

The ^(117m)Sn (Sn⁴⁺) DTPA complex solid may be dissolved in water andoptionally heated, for example in a boiling water bath, to facilitatefurther complexation. The temperature should be sufficient to facilitatecomplexation, without destroying the desired product. Examples of suchtemperature ranges are as achieved in a boiling water bath preferablybetween about 90° C. to about 100° C. If a heating step is performed,the ^(117m)Sn (Sn⁴⁺) DTPA solution may be cooled to approximately roomtemperature prior to use. The pH of the solution containing ^(117m)Sn(Sn⁴⁺) DTPA may be adjusted to between about 3 to about 5, preferablybetween about 4 to about 4.5. The solution may be reheated and cooled.

The resulting pharmaceutical composition ^(117m)Sn (Sn⁴⁺) DTPA may havea molar ratio of DTPA to ^(117m)Sn (Sn⁴⁺) of between about 3 to about 1.That is, in the pharmaceutical composition, for each mole of ^(117m)Sn(Sn⁴⁺) (or total tin) there will be from about one to about three molesof DTPA, either chelated to ^(117m)Sn (Sn⁴⁺) or in unchelated form. Forexample, the resulting pharmaceutical composition ^(117m)Sn (Sn⁴⁺) DTPAmay contain from about one to about 1.2 moles of DTPA for each mole of^(117m)Sn (Sn⁴⁺).

The pharmaceutical composition ^(117m)Sn (Sn⁴⁺) DTPA may optionallyinclude the addition of an isotonic vehicle such as Sodium ChlorideInjection, Ringer's Injection, Dextrose Injection, Dextrose and SodiumChloride Injection, Lactated Ringer's Injection, or other vehicle asknown in the art. The pharmaceutical composition may also include theaddition of stabilizers, preservatives, buffers, or other additivesknown to those of skill in the art.

The following descriptions serve to provide exemplary embodiments of theinvention. Unless specified otherwise, all reagents are high purity,analytical grade or HPLC grade reagents that are available fromcommercial sources. The highly enriched ¹¹⁶Cd, (>99.9 wt %cadmium, >98.4 isotopic % cadmium-116) was purchased from Trace SciencesInternational Inc. Wilmington, Del. The specific activity (Ci/g) of thecyclotron produced NCA ^(117m)Sn was determined by high purity Gedetector. The chemical purity, including the content of other metals,was determined by inductively-coupled plasma (ICP) analysis on a VarianVistaPro ICP-OES.

EXAMPLE 1

TARGET PREPARATION—A solution of highly enriched ¹¹⁶Cd was prepared bydissolving 2 grams of the highly enriched ¹¹⁶Cd in 60 mL of 0.6 Nsulfuric acid. The solution was placed in a plating cell, in contactwith a clean copper target. A power supply was connected to the targetsolution and the solution electrode such that the negative terminal wasattached to the target and the positive terminal was attached to thesolution electrode. The current was set to a range of about 60 mA toabout 100 mA and the target was plated over a period of about 3 hours.Periodically, the process was halted to determine the mass of ¹¹⁶Cdplated on the target until a mass of about 1.1 g to about 1.2 g wasachieved. The ¹¹⁶Cd-electroplated target was stored in a dessicatorunder vacuum until use.

NCA ^(117m)Sn PRODUCTION—Irradiation was performed with 47.3 MeVα-particles on the MC50 cyclotron at the University of WashingtonMedical Center in Seattle, Wash. Initially low beam currents were usedfor to evaluate the activity, specific activity and by-product mixture.After bombardment, the irradiated target was allowed to rest to allowshort-lived products to decay away, then the sample was measured with ahigh-purity Ge detector to determine activity. At this point, ^(117m)Snis the overwhelmingly dominant radioactive product. The only significantother radioactive products in the irradiated cadmium target materialwere ¹¹⁵Cd, ¹¹¹In and to a lesser extent, ^(115m)Cd. The ¹¹³Sn and otherby-products were at the limit of detection, being below 0.1%.

Subsequently, longer (up to 12 hrs) irradiations were made withincreasing beam currents up to 91 μA without any substantial loss oftarget material. Yields were found to be linear with integrated beam,typically in the region of 170 μCi/μA h. A typical 10-hr irradiation at70 μA yielded about 120 mCi. The specific activity range was typicallybetween about 1000 to about 5000 Ci/g at end of bombardment (EOB)although values as high as about 23,000 Ci/g (EOB) were measured in thefinal radiochemical product. Varying specific activity numbers canresult from even trace quantities of environmental tin beinginadvertently introduced during the chemical processing.

SEPARATION BY ION EXCHANGE CHROMATOGRAPHY—After irradiation, the^(117m)Sn was separated from the target material and other contaminantsusing an ion exchange resin column. A 1.1 gram irradiated cadmium targetlayer was removed from the copper backing material by dissolving inapproximately 100 mL of 4 N hydrochloric acid heated to 60° C. Thetarget layer was dissolved over a 1.5 hour etching period. Care wastaken to minimize exposing the copper backing material to the acidsolution. The resulting solution was then evaporated to near dryness at60° C. using blower-assisted evaporation. Concentrated HNO₃ wasintroduced throughout the evaporation to ensure conversion of all thetin species to the +4 oxidation state. The residue was dissolved in 20mL of concentrated HNO₃ and 5 mL of 30% H₂O₂, followed by evaporation tonear dryness and redissolving in a minimum of 9 N HCl. The resultingsolution was then loaded onto an ion exchange resin column comprisingAG1X4 resin (column size=3 cm×50 cm column; 160 grams of BioRad AG1-X4resin slurried in 100 mL of 9 N HCl to which was added 16 grams of solidNaBrO₃) pretreated with 250 mL of 9 N HCl under a gravity flow rate. Theelution order of the major constituents was copper, tin, and cadmium,respectively. The fraction containing copper was eluted in the first 150mL to 200 mL of 0.1 N HNO₃ passed through the column. When ^(117m)Snactivity was detected, the fractions containing tin were collected overa 500 mL to 600 mL elution to recover approximately 80% of the ^(117m)Snactivity. The remaining 20% of ^(117m)Sn activity was eluted in 400 mLof 0.1 N HNO₃, accompanied by cadmium break-through. This^(117m)Sn-cadmium fraction may be subjected to a second ion exchangecolumn purification to maximize isolation of ^(117m)Sn. The^(117m)Sn-containing fractions were concentrated to near dryness underdryer assisted evaporation, while an HCl replacement was performed with80 mL of 8 N HCl to ensure conversion of ^(117m)Sn⁴⁺ to the ^(117m)SnCl₄species. The resulting residue was redissolved in about 1 mL of 1 N HClto provide a product enriched in ^(117m)Sn as a 1.0 mL sample containing31.3 mCi ^(117m)Sn having a specific activity of 10,200 Ci/g Sn with0.1% by activity ¹¹³Sn. This product enriched in NCA ^(117m)Sn had acadmium concentration of about 1 mg/L and had a mass ratio of Cd-to-Snof less than 1:1.

SEPARATION BY LIQUID-LIQUID EXTRACTION—After irradiation, the ^(117m)Snwas separated from the target material and other contaminants byliquid-liquid extraction. A 1.1 gram irradiated cadmium target layer wasremoved from the copper backing material by dissolving in approximately100 mL of 4 N hydrochloric acid heated to 60° C. The target layer wasdissolved over a 1.5 hour etching period. Care was taken to minimizeexposing the copper backing material to the acid solution. The resultingsolution was extracted by mixing with 3×20 mL of hexone(4-methyl-pentan-2-one) that had been pre-equilibrated with 2 N HCl. Theorganic layers containing the bulk of the ^(117m)Sn were combined andthen back-extracted with 3×20 mL 0.05 N HCl. The aqueous back-extractionlayers were combined together, evaporated to near dryness under dryerassisted evaporation and the resulting residue was redissolved in about40 mL of 2 N HCl and the hexone extraction procedure was repeated. Thecombined back-extraction layers were evaporated to near dryness underdryer assisted evaporation and resulting residue was redissolved inabout 2 mL of 6 N HCl to provide a 2.1 mL sample containing 14.3 mCi^(117m)Sn having a specific activity of 15,580 Ci/g Sn with less than0.1% by activity ¹¹³Sn. This product enriched in NCA ^(117m)Sn had acadmium concentration less than 570 mg/L and had a mass ratio ofCd-to-Sn of about 1,300.

While various embodiments of the invention have been described inconsiderable detail, it is not the intention of the applicants torestrict or in any way limit the scope of the appended claims to suchdetail. Additional advantages and modifications will readily appear tothose skilled in the art. The invention in its broader aspects istherefore not limited to the specific details, representative methods,and illustrative examples shown and described. Accordingly, departuresmay be made from such details without departing from the spirit or scopeof applicants' general inventive concept.

What is claimed is:
 1. A composition of matter comprising: ^(117m)Snwith a specific activity greater than 100 Ci/g, and cadmium, wherein amass ratio of all cadmium isotopes in the composition to all tinisotopes in the composition is less than 100 to
 1. 2. The composition ofclaim 1 wherein the ^(117m)Sn has a specific activity ranging from about500 Ci/g to about 25,000 Ci/g.
 3. The composition of claim 1 furthercomprising: ¹¹³Sn in an amount less than 5% by specific activity.
 4. Thecomposition of claim 1 further comprising: ¹¹³Sn in an amount less than0.1% by specific activity.
 5. The composition of claim 1 furthercomprising: at least one ligand combined with the ^(117m)Sn to form aradiopharmaceutical composition.
 6. The composition of claim 1 furthercomprising: at least one chelating agent or at least one targetingmolecule combined with the ^(117m)Sn to form a radiopharmaceuticalcomposition.
 7. The composition of claim 1 further comprising:1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) combinedwith the ^(117m)Sn to form a radiopharmaceutical composition.
 8. Thecomposition of matter of claim 1, wherein the cadmium content is lessthan 20 micrograms per millicurie of ^(117m)Sn; an iron content is lessthan 2 micrograms per millicurie of ^(117m)Sn; and each other metalpresent in the sample was less than 3 micrograms per millicurie of^(117m)Sn, per species.